Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer
Introduction
The treatment of advanced non-small cell lung cancer (NSCLC), which encompasses a number of different histological subtypes [1], remains one of the great challenges of contemporary medical oncology. Approximately 40% of patients with NSCLC present with unresectable metastatic stage IV tumors [2], [3]. Systemic chemotherapy (with or without bevacizumab) or tyrosine kinase inhibitor (TKI) therapy (in particular for patients whose tumors have activating mutations of the epidermal growth factor receptor gene [EGFR]) represent the primary treatment options to extend survival and improve quality of life for this patient group [4], [5], [6], [7], [8], [9], [10], [11]. In the majority of patients of good performance status, first-line chemotherapy regimens generally are based on cytotoxic doublets comprising a platinum analog combined with either vinorelbine, gemcitabine, docetaxel, paclitaxel, or pemetrexed (only for patients with non-squamous disease). A series of randomized trials has suggested that the different standard doublets provide similar levels of efficacy in the first-line treatment of NSCLC [12], [13], [14], [15], [16].
The addition to first-line doublets of a third, concurrently administered, cytotoxic agent has been shown to increase toxicity without improving overall survival [5], [13], [17]. However, the phase III First-Line ErbituX in lung cancer (FLEX) trial in patients with EGFR-expressing NSCLC showed that combining the EGFR antibody cetuximab with cisplatin and vinorelbine significantly improved overall survival in this setting (hazard ratio, HR, 0.871, 95% CI 0.762–0.996; p = 0.044) [18]. Enrollment of the 1125 patients included in the intention-to-treat (ITT) population of this large multinational trial was independent of NSCLC histology but required some degree of tumor EGFR protein expression. A second phase III trial exploring chemotherapy plus cetuximab in this setting, BMS099, which included an ITT population of 676 patients with advanced NSCLC, reported a survival benefit of similar magnitude for the addition of cetuximab to taxane (paclitaxel or docetaxel) plus carboplatin chemotherapy compared with chemotherapy alone (HR 0.89, 95% CI 0.75–1.05; median 9.7 vs 8.4 months), although in this case, the difference between the treatment arms was not statistically significant (p = 0.169) [19]. Tumor EGFR expression was not an eligibility requirement in the BMS099 trial.
We performed a meta-analysis of individual patient data from randomized trials in which chemotherapy plus cetuximab was compared with chemotherapy alone in the first-line treatment of advanced NSCLC. Meta-analyses of individual patient data can offer certain advantages over those based on aggregate or summary data [20]; in particular, the use of individual patient data allows for a more complete analysis, including the study of interaction between the treatment effect and covariates [21]. Our intention was to provide an overall appraisal of the benefit/risk ratio associated with the addition of cetuximab to platinum-based chemotherapy as first-line treatment for advanced NSCLC and to explore treatment outcome in subgroups defined by baseline characteristics of particular interest.
Section snippets
Selected trials
Four randomized trials which compared platinum-based chemotherapy with or without cetuximab as first-line treatment for patients with advanced NSCLC have been reported [18], [19], [22], [23]. Individual patient efficacy and safety data from these four trials were included in the current meta-analysis. Subsequent electronic searches of publication databases did not identify any relevant additional trials that were eligible for inclusion.
Individual patient data
Individual patient data were collected for all patients in
Selected trials and inclusion criteria
Four open-label randomized trials, contributing a total of 2018 ITT patients corresponding to 100% of the randomized patients, were included in the meta-analysis, with 1003 patients randomly assigned to receive chemotherapy plus cetuximab and 1015 to receive chemotherapy alone [18], [19], [22], [23]. Treatment regimens and trial characteristics are summarized in Table 1. The combined safety population, which corresponded to 100% of the patients starting protocol treatment in each of the four
Discussion
The current meta-analysis, which was based on 2018 patients, 56% of whom were enrolled in the phase III FLEX trial, confirmed for all efficacy endpoints a modest benefit associated with the addition of cetuximab to standard platinum-based doublets in the first-line treatment of advanced NSCLC. Three published meta-analyses [26], [27], [28] based on aggregate data from the same four randomized trials reached similar conclusions to the current study regarding the benefit of adding cetuximab to
Conclusion
As suggested by the absence of significant heterogeneity between trials, this meta-analysis has demonstrated a consistent benefit in all efficacy endpoints for the addition of cetuximab to standard, platinum-based chemotherapy doublets used in the first-line treatment of advanced NSCLC. The meta-analysis also demonstrates that the safety profile of chemotherapy plus cetuximab in this setting compared with chemotherapy alone is acceptable.
Conflict of interest statement
Regarding the work under consideration: J-LP declared receiving a consultancy fee/honorarium and support for travel to meetings from Merck Serono; RP, KJO’B and NT declared receiving consultancy fees/honoraria, support for travel to meetings and fees for participating in reviews of study results from Merck Serono; TJL declared receiving support for travel to meetings from Bristol-Myers Squib (BMS); CAB declared receiving per case funding for the original trial from study sponsor BMS and
Funding sources and any writing assistance
The sponsor of this study, Merck KGaA, Darmstadt, Germany, was responsible for statistical analysis. Data were interpreted by the sponsor in collaboration with the authors. The sponsor commissioned the drafting of our report. Jim Heighway of Cancer Communications & Consultancy Ltd. (Knutsford, UK) provided medical writing services, which were funded by the sponsor. J-LP had the final responsibility for the decision to submit the manuscript for publication.
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